EP2318005A1 - Agents neuroprotecteurs pour la prévention et le traitement de maladies neurodégénératives - Google Patents

Agents neuroprotecteurs pour la prévention et le traitement de maladies neurodégénératives

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Publication number
EP2318005A1
EP2318005A1 EP09803262A EP09803262A EP2318005A1 EP 2318005 A1 EP2318005 A1 EP 2318005A1 EP 09803262 A EP09803262 A EP 09803262A EP 09803262 A EP09803262 A EP 09803262A EP 2318005 A1 EP2318005 A1 EP 2318005A1
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Prior art keywords
alkyl
alkenyl
alkynyl
independently
compound
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EP09803262A
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German (de)
English (en)
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EP2318005B1 (fr
EP2318005A4 (fr
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John S. Kovach
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Lixte Biotechnology Inc
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Lixte Biotechnology Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • AD Alzheimer's disease
  • Akt kinase has beneficial effects upon neurons of the substantia nigra of the midbrain of animals.
  • AD and other neurodegenerative diseases are called tauopathies because they are characterized by the accumulation of aggregates of the tau protein in neurons .
  • Tau proteins promote the assembly and stabilization of microtubular structures in neurons .
  • the function of tau is regulated by phosphorylation at multiple serine and threonine sites (Sontag et al 1996; Tian and Wang 2002) .
  • the state of phosphorylation of tau influences its ability to bind to and enhance the polymerization of microtubules in neurons (Gong et al 2005; Meske et al 2008) .
  • Control of tau activity by phosphorylation is accomplished by several serine-threonine kinases, particularly glycogen synthase kinase-3 ⁇ (GSK-3 ⁇ ) .
  • GSK-3 ⁇ itself is regulated by other serine- threonine kinases especially Akt (Grimes and Jope 2001; Liu et al 2005) .
  • Akt glycogen synthase kinase-3 ⁇
  • Akt glycogen synthase kinase-3 ⁇
  • Baki et al 2004 showed that there was inadequate PI3K-Akt signaling resulting in decreased phosphorylation of GSK-3 ⁇ , hyper-phosphorylation of tau, and progressive neurodegeneration.
  • the addition of normal presenilin-1 or of PI3K-Akt increased GSK-3 ⁇ phosphorylation and suppressed neuronal cell death.
  • HDACi Histone deacetylase inhibitors
  • AD Alzheimer's disease
  • P2Ai protein phosphatase 2A
  • okadaic acid primarily the shellfish toxin, okadaic acid
  • AD is a pathologic condition resulting from inadequate activity of the enzyme Akt and excessive activity of GSK-3 ⁇ and that reduction of GSK-3 ⁇ activity may reduce the severity of precipitated tau proteins, with a lessening of neurological deficit.
  • GSK-3 ⁇ activity may reduce the severity of precipitated tau proteins, with a lessening of neurological deficit.
  • GSK-3 ⁇ activity may reduce the severity of precipitated tau proteins, with a lessening of neurological deficit.
  • neurodegenerative diseases related to excessive histone deacetylase activity or at least a condition of reduced acetylation of certain histones that is corrected by increased acetylation resulting in improved learning and memory.
  • Non-toxic drugs that protect and foster the survival of acute and chronically diseased neurons are urgently needed.
  • the compounds described herein reduce the activity of GSK-3 ⁇ and increase the acetylation of neuronal histones.
  • This invention disclosed herein provides a method of treating a subject with a neurodegenerative disease comprising administering to the subject a compound having the structure
  • Rn is independently alkyl, alkenyl or alkynyl, each of which is substituted or unsubstituted, or H;
  • R 7 and Rs is each independently H, F, Cl, Br, SO 2 Ph, CO 2 CH 3 , or SRi 2 , where Ri 2 is H, aryl or a substituted or unsubstituted alkyl, alkenyl or alkynyl, or a salt, enantiomer or zwitterion of the compound, or a compound having the structure
  • This invention also provides a method for reducing the amount of GSK-3 ⁇ in a neural cell comprising contacting the cell with an effective amount of a compound having the structure wherein bond ⁇ is present or absent;
  • Rn is independently alkyl, alkenyl or alkynyl, each of which is substituted or unsubstituted, or H;
  • R 7 and R 8 is each independently H, F, Cl, Br, SO 2 Ph, CO 2 CH 3 , or SR12, where R 12 is H, aryl or a substituted or unsubstituted alkyl, alkenyl or alkynyl,or a salt, enantiomer or zwitterion of the compound, or a compound having the structure
  • n 1-10;
  • Y is C-R 30 or N, wherein R 30 is H, OH, SH, F, Cl, SO 2 R 26 , NO 2 , trifluoromethyl, methoxy, or CO-R 2 6/ wherein R 2 6 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl;
  • Z is
  • R21 is H or NR 22 R 23 / wherein R22 and R2 3 are each independently H, Ci-C ⁇ alkyl, or C 3 -C 8 cycloalkyl; R 24 is OH or SH; and R 25 , R 3x , R 32 , and R 33 are each independently H, OH, SH, F, Cl, SO 2 R 34 , NO 2 , trifluoromethyl, methoxy, or CO-R 34 , wherein R 34 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl, or a salt of the compound, so as to thereby reduce the amount of GSK-3 ⁇ in the neural cell.
  • Rn is independently alkyl, alkenyl or alkynyl, each of which is substituted or unsubstituted, or H
  • R 7 and R 8 is each independently H, F, Cl, Br, SO 2 Ph, CO 2 CH 3 , or SR 12 , where R 12 is H, aryl or a substituted or unsubstituted alkyl, alkenyl or alkynyl,or a salt, enantiomer or zwitterion of the compound, or a compound having the structure
  • This invention further provides a method for reducing the phosphorylation of tau in a neural cell, comprising contacting the neural cell with an effective amount of a compound having the structure
  • Rn is independently alkyl, alkenyl or alkynyl, each of which is substituted or unsubstituted, or H;
  • R 7 and R 8 is each independently H, F, Cl, Br, SO 2 Ph, CO 2 CH 3 , or SRi 2 , where Ri 2 is H, aryl or a substituted or unsubstituted alkyl, alkenyl or alkynyl, or a salt, enantiomer or zwitterion of the compound, or a compound having the structure
  • R 2 6 is alkyl, alkenyl, alkynyl, C 3 -Ce cycloalkyl, or aryl
  • Z is R21 is H or NR 22 R 23 , wherein R 22 and R 23 are each independently H, Ci-C ⁇ alkyl, or C 3 -Cs cycloalkyl
  • R 24 is OH or SH
  • R 25 , R 31 , R 32 , and R 33 are each independently H, OH, SH, F, Cl, SO 2 R 34 , NO 2 , trifluoromethyl, methoxy, or CO-R 34 , wherein R 34 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl, or a salt of the compound, so as to thereby reduce the phosphorylation of tau in the neural cell.
  • Figure 1 Induction of phosphorylated Akt by Compound 100 in DAOY cells in culture.
  • the medulloblastoma cells, DAOY, in culture were exposed to Compound 100, Compound 205 or vehicle alone. After 4 hours western blots were made for p- Akt, total Akt, and beta actin. Control cells (C) showed only trace amounts of p-Akt and substantial amounts of total Akt and beta actin. Exposure to Compound 205, a compound with no anti-PP2A activity, had no effect. Exposure to Compound 100 revealed induction of p-Akt and an increase in total Akt relative to beta actin.
  • FIG. 1 Induction of phosphorylated Akt by Compound 100 in DAOY cells growing as xenografts in SCID mice.
  • SCID mice with human medulloblastoma cells, DAOY, implanted subcutaneousIy were treated with 0.03 mg/20 gram mouse with Compound 100 or vehicle alone. After 4 hours and 24 hours western blots were made for p-Akt, total Akt, and beta actin. Control cells (C) at both time points (only 24 hour point shown) had only trace amounts of p-Akt and substantial amounts of total Akt and beta actin. Exposure to Compound 100 revealed induction of p-Akt and an increase in total Akt relative to beta actin.
  • Figure 3 Induction of phosphorylated Akt by Compound-100 in U87 cells in culture.
  • Figure 4 Induction of phosphorylated Akt by Compound-100 in U87 cells growing as xenografts in SCID mice.
  • SCID mice with human glioblastoma cells, U87, implanted subcutaneousIy were treated with 0.03 mg/20 gram mouse with Compound 100 or vehicle alone.
  • Figure 5 Induction of acetylation of Histone 3 and Histone 4 in normal mouse brain by Compound 100 and Compound
  • mice Normal mice were treated with Compound 100 and Compound 102, 0.03 mg/20 gram mouse. After 4 hours of exposure, treated and control animals (vehicle alone) animals were sacrificed and western blots for acetylated histone 3 and histone 4 were made. Both drugs increased acetylation of the histones compared to control tissue.
  • FIG. 1 Photomicrographs of primary embryonal rat cortical neuronal cells at 23 days subjected to environmental stress by exposure to growth factor deficient medium for 1 hour on day 3 of culture.
  • FIGS 8-10 Calcium response to acute exposure of 20OuM glutax ⁇ ate in the presence of vehicle (0.05% DMSO) .
  • Figure 8 shows photomicrographs of one field of cells in which change in calcium flux was measured in individual cells (Figure 9), and then averaged ( Figure 10) .
  • FIGs 11-14 Calcium response to acute exposure to 20OuM glutamate in the presence of 500nm Compound 102.
  • Figure 11 shows photomicrographs of one field of cells in which change in calcium flux was measured in individual cells (Figure 12), then averaged ( Figure 13), and the average response was compared to the DMSO control ( Figure 14) .
  • Figures 15-18 Calcium response to acute exposure to 20OuM glutamate in the presence of 500nm Compound 201.
  • Figure 15 shows photomicrographs of one field of cells in which change in calcium flux was measured in individual cells (Figure 16), then averaged ( Figure 17) , and the average response was compared to the DMSO control ( Figure 18) .
  • This invention provides a method of treating a subject with a neurodegenerative disease comprising administering to the subject a compound having the structure
  • R 3 and R 4 are each different, and each is OH, 0 " , ORg, SH, S " , SR 9 ,
  • each Rn is independently alkyl, alkenyl or alkynyl, each of which is substituted or unsubstituted, or H;
  • R 7 and Rs is each independently H, F, Cl, Br, SO 2 Ph, CO 2 CH 3 , or SRi 2 , where R i2 is H, aryl or a substituted or unsubstituted alkyl, alkenyl or alkynyl, or a salt, enantiomer or zwitterion of the compound, or a compound having the structure
  • n 1-10;
  • Y is C-R 30 or N, wherein R 30 is H, OH, SH, F, Cl, SO2R26, NO 2 , trifluoromethyl, methoxy, or CO-R2 6 , wherein R26 is alkyl, alkenyl, alkynyl, C 3 -Cs cycloalkyl, or aryl;
  • R21 is H or NR 22 R 23 / wherein R 22 and R 23 are each independently H, Ci-C 6 alkyl, or C 3 -Cs cycloalkyl; R 24 is OH or SH; and
  • R25, R 3 i/ R32/ and R 33 are each independently H, OH, SH, F, Cl, SO 2 R 34 , NO 2 , trifluoromethyl, methoxy, or CO-R 34 , wherein R 34 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl, or a salt of the compound, in an amount effective to treat the subject.
  • the compound has the structure
  • n 1-9;
  • Y is C-R 30 or N, wherein R 30 is H, OH, SH, F, Cl, SO 2 R 2 6, NO 2 , trifluoromethyl, methoxy, or CO-R 26 , wherein R 2 6 is alkyl, alkenyl, alkynyl, C 3 -Cs cycloalkyl, or aryl;
  • R 21 is H or NR 22 R 23 , wherein R 22 and R 23 are each independently
  • Ci-C 6 alkyl or C 3 -C 8 cycloalkyl
  • R 24 is OH or SH
  • R25/ R3 1 / R 32 / and R 33 are each independently H, OH, SH, F,
  • R 34 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl.
  • the compound has the structure
  • n 1-8;
  • Y is CH or N
  • R 2 O is H or OH
  • R 21 is H or NR 22 R 2 3/ wherein R 22 and R 23 are each independently
  • R 24 is OH or SH
  • R 25 is H, OH, SH, F, Cl, SO2R26, NO 2 , trif luoromethyl , methoxy, or CO-R 26/ wherein R 26 is alkyl, alkenyl, alkynyl,
  • the compound has the structure
  • n 1-9;
  • Y is C-R 30 or N, wherein R 30 is H, OH, SH, F, Cl, SO 2 R 26 , NO 2 , trifluoromethyl , methoxy, or CO-R 26 , wherein R 26 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl; R 2I is H or NR 22 R 23 / wherein R 22 and R 23 are each independently
  • Ci-C 6 alkyl or C 3 -C 8 cycloalkyl ;
  • R 24 is OH or SH ;
  • R 2 5 R31, R 3 2/ and R 33 are each independently H, OH, SH, F, Cl, trifluoromethyl , methoxy, or CO-R 34 , wherein R 34 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl; In further embodiment, the compound has the structure
  • n 1-8;
  • Y is CH or N
  • R20 is H or OH
  • R21 is H or NR 22 R 23 / wherein R 22 and R 23 are each independently
  • R24 is OH or SH
  • R25 is H, OH, SH, F, Cl, trifluoromethyl , methoxy, or CO-R 26 , wherein R 26 is alkyl, alkenyl, alkynyl, or C 3 -C 8 cycloalkyl, or aryl .
  • the compound has the structure
  • n 1 - 8 ;
  • Y is CH or N ;
  • R21 is H or NR 22 R 23 / wherein R 22 and R 23 are each independently Ci-C 6 alkyl or C 3 -Cs cycloalkyl; R 24 is OH or SH; and
  • R 25 is H, OH, SH, F, Cl, trifluoromethyl , methoxy, or CO-R 2 6, wherein R 26 is alkyl, alkenyl, alkynyl, or C 3 -Cs cycloalkyl, or aryl .
  • subject is a mammal.
  • the neurodegenerative disease is Alzheimer's disease, Mild Cognitive Impairment, Parkinsons Disease, Frontotemporal Dementia, Dementia, or Lewy Body Dementia. In a further embodiment the neurodegenerative disease is Alzheimer's disease.
  • Another embodiment of the above method further comprises administering to the subject an NMDA receptor antagonist, an acetylcholinesterase inhibitor, an anti-amyloid antibody, a 5- HT6 antagonist, a gamma secretase inhibitor, a beta secretase inhibitor, or an inhibitor of aggregation of amyloid- ⁇ peptide.
  • the method further comprises administering to the subject a tau aggregation inhibitor.
  • Examples of known NMDA receptor agonists include, but are not limited to, memantine.
  • Examples of known acetylcholinesterase inhibitors include, but are not limited to, galantamine, rivastigmine, and donapezil.
  • Examples of a tau aggregation inhibitor include, but are not limited to, rember.
  • the neurodegenerative disease is Parkinson's disease.
  • Another embodiment of the above method further comprises administering to the subject a dopamine receptor agonist.
  • the invention provides a method for reducing the amount of active GSK-3B in a neural cell comprising contacting the cell with an effective amount of a compound having the structure
  • R 3 and R 4 are each different, and each is OH, CT, ORg, SH, S " , SR 9 ,
  • each Rn is independently alkyl, alkenyl or alkynyl, each of which is substituted or unsubstituted, or H;
  • R 7 and R 8 is each independently H, F, Cl, Br, SO 2 Ph, CO 2 CH 3 , or SRi 2 , where R i2 is H, aryl or a substituted or unsubstituted alkyl, alkenyl or alkynyl, or a salt, enantiomer or zwitterion of the compound, or a compound having the structure
  • n 1-10 ;
  • Y is C-R 30 or N, wherein R 30 is H, OH, SH, F, Cl, SO 2 R 26 , NO 2 , trifluoromethyl, methoxy, or CO-R 2 6, wherein R 2 6 is alkyl, alkenyl, alkynyl, C 3 -Ca cycloalkyl, or aryl;
  • R 2 i is H or NR 22 R 23/ wherein R 22 and R 23 are each independently H, C x -C 6 alkyl, or C 3 -C 8 cycloalkyl; R 24 is OH or SH; and
  • R 2 5/ R 3 i/ R 32 / and R 33 are each independently H, OH, SH, F, Cl, SO 2 R 34 , NO 2 , trif luoromethyl, methoxy, or CO-R 34 , wherein R 34 is alkyl, alkenyl, alkynyl, C 3 -Cs cycloalkyl, or aryl, or a salt of the compound, so as to thereby reduce the amount of GSK-3B in the neural cell.
  • the compound has the structure
  • n 1-9;
  • Y is C-R 30 or N, wherein R 30 is H, OH, SH, F, Cl, SO 2 R 2 6, NO 2 , trif luoromethyl , methoxy, or CO-R 26 / wherein R 26 is alkyl, alkenyl, alkynyl, C 3 -Cs cycloalkyl, or aryl;
  • R 21 is H or NR 22 R 23 , wherein R 22 and R 23 are each independently
  • Ci-C 6 alkyl or C 3 -C 8 cycloalkyl
  • R 24 is OH or SH
  • R25/ R 3 i/ R 32 / and R 33 are each independently H, OH, SH, F,
  • R 34 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl.
  • the compound has the structure
  • n is 1- 8 ;
  • Y is CH or N
  • R20 is H or OH ;
  • R 2 i is H or NR 22 R 23 / wherein R 22 and R 23 are each independently
  • Ci-C 6 alkyl or C 3 -Cs cycloalkyl are Ci-C 6 alkyl or C 3 -Cs cycloalkyl ;
  • R 24 is OH or SH ;
  • R25 is H, OH, SH, F, Cl, SO 2 R 2 6, NO 2 , trifluoromethyl , methoxy, or CO-R 26 , wherein R 2 6 is alkyl, alkenyl, alkynyl,
  • the compound has the structure
  • n is 1- 9 ;
  • Y is C-R 30 or N, wherein R 30 is H, OH, SH, F, Cl, SO 2 R 26 , NO 2 , trifluoromethyl, methoxy, or CO-R 26 , wherein R 26 is alkyl, alkenyl, alkynyl, C 3 -Cs cycloalkyl, or aryl; R 2 i is H or NR 22 R 2 3 , wherein R 22 and R23 are each independently
  • Ci-C 6 alkyl or C 3 -C 8 cycloalkyl ;
  • R 24 is OH or SH ;
  • R2 5 / R 3 1/ R 32 / and R 33 are each independently H, OH, SH, F, Cl, trifluoromethyl, methoxy, or CO-R 34 , wherein R 34 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl ;
  • the compound has the structure
  • n 1-8;
  • Y is CH or N
  • R 20 is H or OH
  • R 2 i is H or NR2 2 R2 3 / wherein R 22 and R 23 are each independently
  • R 24 is OH or SH
  • R 25 is H, OH, SH, F, Cl, trifluoromethyl , methoxy, or CO-R 26 , wherein R 26 is alkyl, alkenyl, alkynyl, or C 3 -C 8 cycloalkyl, or aryl .
  • the compound has the structure
  • R 20 is H or OH
  • R 2 i is H or NR 22 R 23 / wherein R 22 and R 23 are each independently
  • R 24 is OH or SH
  • R 2 5 is H, OH, SH, F, Cl, trif luoromethyl , methoxy, or CO-R 26 / wherein R 26 is alkyl, alkenyl, alkynyl, or C 3 -Cs cycloalkyl, or aryl.
  • each Rn is independently alkyl, alkenyl or alkynyl, each of which is substituted or unsubstituted, or H;
  • R 7 and R 8 is each independently H, F, Cl, Br, SO 2 Ph, CO 2 CH 3 , or SR12, where R 12 is H, aryl or a substituted or unsubstituted alkyl, alkenyl or alkynyl, or a salt, enantiomer or zwitterion of the compound, or a compound having the structure wherein n is 1-10 ;
  • Y is C-R 30 or N, wherein R 30 is H, OH , SH , F , Cl , SO2R26 , NO 2 , tri f luoromethyl , methoxy, or CO-R 26 / wherein R 26 is alkyl , alkenyl , alkynyl , C 3 -Cs cycloalkyl , or aryl ;
  • R21 is H or NR22R23/ wherein R22 and R23 are each independently H, Ci-C 6 alkyl, or C 3 -C 8 cycloalkyl; R 24 is OH or SH; and
  • R25/ R31/ R32/ and R3 3 are each independently H, OH, SH, F, Cl, SO2R 3 4, NO 2 , trifluoromethyl, methoxy, or CO-R 34 , wherein R 34 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl, or a salt of the compound, so as to thereby increase the amount of phosphorylated Akt in the neural cell.
  • the compound has the structure
  • n 1-9;
  • Y is C-R 30 or N, wherein R 30 is H, OH, SH, F, Cl, SO 2 R 26 , NO 2 , trif luoromethyl, methoxy, or CO-R 26/ wherein R 26 is alkyl, alkenyl, alkynyl, C 3 -Cs cycloalkyl, or aryl;
  • R 2 i is H or NR 22 R 23 , wherein R 22 and R 23 are each independently
  • Ci-C 6 alkyl or C 3 -Cs cycloalkyl
  • R 24 is OH or SH
  • R-25/ R 3 i/ R 32 , and R 33 are each independently H, OH, SH, F,
  • R 34 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl.
  • the compound has the structure
  • n 1-8;
  • Y is CH or N
  • R 20 is H or OH
  • R 2 i is H or NR 22 R 23 , wherein R 22 and R 23 are each independently
  • R 24 is OH or SH
  • R 25 is H, OH, SH, F, Cl, SO 2 R 26 , NO 2 , trifluoromethyl , methoxy, or CO-R 26 , wherein R 26 is alkyl, alkenyl, alkynyl,
  • the compound has the structure
  • n 1-9;
  • Y is C-R 30 or N, wherein R 30 is H, OH, SH, F, Cl, SO 2 R 2 e, NO 2 , trifluoromethyl, methoxy, or CO-R 26 , wherein R 2 6 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl;
  • R21 is H or NR 22 R 23 / wherein R 2 2 and R 23 are each independently
  • Ci-C 6 alkyl or C 3 -C 8 cycloalkyl
  • R 24 is OH or SH
  • R25/ R 3 i/ R 32 / and R 33 are each independently H, OH, SH, F, Cl, trifluoromethyl, methoxy, or CO-R 34 , wherein R 34 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl; In further embodiment, the compound has the structure
  • n 1-8;
  • Y is CH or N
  • R 2O is H or OH
  • R 21 is H or NR 22 R 23/ wherein R 22 and R 23 are each independently
  • R 24 is OH or SH; and R25 is H, OH, SH, F, Cl, trifluoromethyl , methoxy, or CO-R26, wherein R 26 is alkyl, alkenyl, alkynyl, or C 3 -Cs cycloalkyl, or aryl.
  • the compound has the structure
  • n is 1- 8 ;
  • Y is CH or N
  • R20 is H or OH ;
  • R21 is H or NR 22 R 2 3 / wherein R22 and R 2 3 are each independently
  • Ci-C 6 alkyl or C 3 -Cs cycloalkyl are Ci-C 6 alkyl or C 3 -Cs cycloalkyl ;
  • R 2 4 is OH or SH ;
  • R2 5 is H, OH, SH, F, Cl, trifluoromethyl , methoxy, or CO-R 2 6, wherein R 26 is alkyl, alkenyl, alkynyl, or C 3 -C 8 cycloalkyl, or aryl.
  • the invention provides a method for reducing the phosphorylation of Tau protein in a cell, comprising contacting the cell with an effective amount of a compound having the structure
  • R 3 and R 4 are each different, and each is OH, 0 " , OR 9 , SH, S " , SR 9 ,
  • each Rn is independently alkyl, alkenyl or alkynyl, each of which is substituted or unsubstituted, or H;
  • R 7 and R 8 is each independently H, F, Cl, Br, SO 2 Ph, CO 2 CH 3 , or SRi 2 , where Ri 2 is H, aryl or a substituted or unsubstituted alkyl , alkenyl or alkynyl, or a salt, enantiomer or zwitterion of the compound, or a compound having the structure
  • n 1-10;
  • Y is C-R 30 or N, wherein R 30 is H, OH, SH, F, Cl, SO 2 R 2 6/ NO 2 , trifluoromethyl, methoxy, or CO-R 26 / wherein R 26 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl;
  • R 21 is H or NR 22 R 23 / wherein R 22 and R 23 are each independently H, Ci-C 6 alkyl, or C 3 -C 8 cycloalkyl; R 24 is OH or SH; and
  • R2 5 / R 3 i, R 32 / and R 33 are each independently H, OH, SH, F, Cl, SO 2 R 34 , NO 2 , trifluoromethyl, methoxy, or CO-R 34 , wherein R 34 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl, or a salt of the compound, so as to thereby reduce the phosphorylation of tau in the cell.
  • the compound has the structure
  • n 1-9;
  • Y is C-R 30 or N, wherein R 30 is H, OH, SH, F, Cl, SO2R26, NO 2 , trifluoromethyl, methoxy, or CO-R 26 , wherein R 26 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl;
  • R 2 i is H or NR 22 R 23 , wherein R 22 and R 23 are each independently H, Ci-C 6 alkyl, or C 3 -C 8 cycloalkyl; R 24 is OH or SH; and
  • R 2 5/ R 3 i/ R 32 , and R 33 are each independently H, OH, SH, F, Cl, SO 2 R 34 , NO 2 , trifluoromethyl, methoxy, or CO-R 34 , wherein R 34 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl.
  • the compound has the structure
  • n 1-8;
  • Y is CH or N
  • R20 is H or OH
  • R 21 is H or NR 22 R 23 , wherein R 22 and R 23 are each independently
  • Ci-C 6 alkyl or C 3 -C 8 cycloalkyl R 24 is OH or SH; and R 25 is H, OH, SH, F, Cl, SO2R26, NO 2 , trifluoromethyl , methoxy, or CO-R 26 , wherein R 26 is alkyl, alkenyl , alkynyl, C 3 -C 8 cycloalkyl, or aryl .
  • the compound has the structure
  • n 1-9;
  • Y is C-R 30 or N, wherein R 30 is H, OH, SH, F, Cl, SO2R26/ NO 2 , trif luoromethyl, methoxy, or CO-R 2 6/ wherein R 26 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl;
  • R 21 is H or NR 22 R 23 , wherein R 22 and R 23 are each independently H, Ci-C 6 alkyl, or C 3 -C 8 cycloalkyl;
  • R 24 is OH or SH
  • R2 5 , R 31 / R 32 / and R 33 are each independently H, OH, SH, F, Cl, trifluoromethyl, methoxy, or CO-R 34 , wherein R 34 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl;
  • the compound has the structure
  • n 1-8;
  • Y is CH or N;
  • R 2 O is H or OH ;
  • R 21 is H or NR 22 R 23 , wherein R 22 and R 23 are each independently
  • Ci-C 6 alkyl or C 3 -C 8 cycloalkyl are Ci-C 6 alkyl or C 3 -C 8 cycloalkyl ;
  • R 24 is OH or SH ;
  • R 25 is H, OH, SH, F, Cl, trifluoromethyl , methoxy, or CO-R26, wherein R 26 is alkyl, alkenyl, alkynyl, or C 3 -Cs cycloalkyl, or aryl .
  • the compound has the structure
  • n is 1- 8 ;
  • Y is CH or N
  • R 20 is H or OH ;
  • R 21 is H or NR 22 R 23 , wherein R 22 and R 23 are each independently
  • Ci-C 6 alkyl or C 3 -C 8 cycloalkyl are Ci-C 6 alkyl or C 3 -C 8 cycloalkyl ;
  • R 24 is OH or SH ;
  • R 25 is H, OH, SH, F, Cl, trifluoromethyl , methoxy, or CO-R 2 6, wherein R 26 is alkyl, alkenyl, alkynyl, or C 3 -C 8 cycloalkyl, or aryl.
  • R 3 and R 4 are each different, and each is OH, 0 " , ORg, SH, S " , SR 9 ,
  • Rn is independently alkyl, alkenyl or alkynyl, each of which is substituted or unsubstituted, or H;
  • R 7 and R 8 is each independently H, F, Cl, Br, SO 2 Ph, CO 2 CH 3 , or SRi 2 , where Ri 2 is H, aryl or a substituted or unsubstituted alkyl, alkenyl or alkynyl, or a salt, enantiomer or zwitterion of the compound, or a compound having the structure
  • n 1-10;
  • Y is C-R 30 or N, wherein R 30 is H, OH, SH, F, Cl, SO 2 R 26 , NO 2 , trifluoromethyl , methoxy, or CO-R 26 , wherein R 26 is alkyl, alkenyl, alkynyl, C 3 -Cs cycloalkyl, or aryl;
  • R 2 i is H or NR 22 R 23 , wherein R 22 and R 23 are each independently H, Ci-C 6 alkyl , or C 3 -C 8 cycloalkyl ;
  • R 24 is OH or SH; and R2 5 / R 3 i/ R 32 / and R 33 are each independently H, OH, SH, F, Cl, SO 2 R 34 , NO 2 , trifluoromethyl, methoxy, or CO-R34, wherein R 34 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl, or a salt of the compound, so as to thereby inhibit the aggregation of Tau in the cell.
  • the compound has the structure
  • n 1-9;
  • Y is C-R 30 or N, wherein R 30 is H, OH, SH, F, Cl, SO 2 R 2 S, NO 2 , trif luoromethyl, methoxy, or CO-R 26 , wherein R 2 6 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl;
  • R 21 is H or NR 22 R 2 3/ wherein R22 and R23 are each independently
  • Ci-C 6 alkyl or C 3 -C 8 cycloalkyl
  • R 24 is OH or SH
  • R25, R 3 1/ R32/ and R 33 are each independently H, OH, SH, F, Cl, SO 2 R 34 , NO 2 , trifluoromethyl, methoxy, or CO-R 34 , wherein
  • R 34 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl.
  • the compound has the structure
  • n is 1- 8 ;
  • Y is CH or N
  • R 20 is H or OH ;
  • R 2 i is H or NR 22 R 23 , wherein R 22 and R 23 are each independently
  • Ci-C 6 alkyl or C 3 -C 8 cycloalkyl are Ci-C 6 alkyl or C 3 -C 8 cycloalkyl ;
  • R 24 is OH or SH ;
  • R 25 is H, OH, SH, F, Cl, SO 2 R 26 , NO 2 , trifluoromethyl , methoxy, or CO-R 26 , wherein R 26 is alkyl, alkenyl, alkynyl,
  • the compound has the structure
  • n 1-9;
  • Y is C-R 30 or N, wherein R 30 is H, OH, SH, F, Cl, SO 2 R 26 , NO 2 , trifluoromethyl, methoxy, or CO-R 26 , wherein R 26 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl; R 2 i is H or NR 22 R 23 , wherein R 22 and R 23 are each independently H, C x -C 6 alkyl, or C 3 -C 8 cycloalkyl; R 24 is OH or SH; and
  • R 25 , R 31 , R 3 2, and R 33 are each independently H, OH, SH, F, Cl, trifluoromethyl , methoxy, or CO-R 34 , wherein R 34 is alkyl, alkenyl, alkynyl, C 3 -C 8 cycloalkyl, or aryl; In further embodiment, the compound has the structure
  • n 1-8;
  • Y is CH or N
  • R 20 is H or OH
  • R 2 i is H or NR 22 R 23 , wherein R 22 and R 23 are each independently
  • R 24 is OH or SH
  • R 25 is H, OH, SH, F, Cl, trifluoromethyl , methoxy, or CO-R 26 , wherein R 26 is alkyl, alkenyl , alkynyl, or C 3 -Cs cycloalkyl, or aryl . other embodiment, the compound has the structure
  • n 1-8;
  • Y is CH or N
  • R 20 is H or OH
  • R 2 i is H or NR 22 R 23 , wherein R 22 and R 23 are each independently
  • R 24 is OH or SH; and R 2 5 is H, OH, SH, F, Cl, trifluoromethyl , methoxy, or CO-R 26 , wherein R 26 is alkyl, alkenyl, alkynyl, or C 3 -Cs cycloalkyl, or aryl.
  • the cell is a neural cell. In another embodiment of the foregoing methods, the cell is in a subject.
  • the compound has structure of Compound 100, Compound 100E, Compound 101, Compound 101E, Compound 102, Compound 102E, Compound 103, Compound 103E, Compound 104, Compound 104E, Compound 105, Compound 105E, Compound 106, Compound 106E, Compound 107, Compound 107E, Compound 108 or Compound 108E.
  • the compound has the structure of Compound 201, Compound 203, Compound 204, Compound 205, Compound 206, Compound 207, Compound 207 (a), Compound 208, Compound 209, Compound 210, Compound 211, Compound 212, Compound 213, or Compound 214.
  • Certain embodiments of the disclosed compounds can contain a basic functional group, such as amino or alkylamino, and are thus capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids, or contain an acidic functional group and are thus capable of forming pharmaceutically acceptable salts with bases.
  • the instant compounds therefore may be in a salt form.
  • a "salt" is a salt of the instant compounds which has been modified by making acid or base salts of the compounds.
  • the salt may be pharmaceutically acceptable.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols.
  • the salts can be made using an organic or inorganic acid.
  • Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like.
  • Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium.
  • pharmaceutically acceptable salt in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention.
  • salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like.
  • suitable salts see, e.g., Berge et al . (1977) "Pharmaceutical Salts", J. Pharm. Sci . 66:1-19.
  • terapéuticaally effective amount means an amount sufficient to treat a subject afflicted with a disease (e.g. a neurodegenerative disease) or to alleviate a symptom or a complication associated with the disease.
  • a disease e.g. a neurodegenerative disease
  • a “neurodegenerative disease” refers to a disease in which degeneration occurs of either gray or white matter, or both, of the nervous system.
  • a disease can be diabetic neuropathy, senile dementias, Alzheimer's disease, Mild Cognitive Impairment (MCI) , dementia, Lewy Body Dementia, Frontal Temporal Lobe dementia, Parkinson's Disease, facial nerve (Bell's) palsy, glaucoma, Huntington's chorea, amyotrophic lateral sclerosis (ALS), status epilepticus, non-arteritic optic neuropathy, intervertebral disc herniation, vitamin deficiency, prion diseases such as Creutzfeldt-Jakob disease, carpal tunnel syndrome, peripheral neuropathies associated with various diseases, including but not limited to, uremia, porphyria, hypoglycemia, Sjorgren Larsson syndrome, acute sensory neuropathy, chronic ataxic neuropathy, biliary cirrhosis, primary
  • tauopathies refers to a class of neurodegenerative diseases which result from aggregation of tau protein in neurofibrillary tangles.
  • tauopathies include, but are not limited to, Alzheimer's disease, Frontotemproal dementia (Pick's disease), Progressive Supranuclear Palsy, and Corticobasal degeneration.
  • treating means slowing, stopping or reversing the progression of a disease, particularly a neurodegenerative disease .
  • zwitterion means a compound that is electrically neutral but carries formal positive and negative charges on different atoms. Zwitterions are polar, have high solubility in water have poor solubility in most organic solvents .
  • the compounds disclosed herein may also form zwitterions
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • Ci-C n as in “Ci-C n alkyl” is defined to include groups having 1, 2, ...., n-1 or n carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, and so on.
  • An embodiment can be Ci-Ci 2 alkyl.
  • Alkoxy represents an alkyl group as described above attached through an oxygen bridge.
  • alkenyl refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non- aromatic carbon-carbon double bonds may be present.
  • C 2 -C n alkenyl is defined to include groups having 1, 2, ...., n-1 or n carbons.
  • C 2 -C 6 alkenyl means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and at least 1 carbon- carbon double bond, and up to, for example, 3 carbon-carbon double bonds in the case of a C 6 alkenyl, respectively.
  • Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl . As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated. An embodiment can be C 2 -Ci 2 alkenyl .
  • alkynyl refers to a hydrocarbon radical straight or branched, containing at least 1 carbon to carbon triple bond, and up to the maximum possible number of non-aromatic carbon- carbon triple bonds may be present.
  • C 2 -C n alkynyl is defined to include groups having 1, 2, ...., n-1 or n carbons.
  • C 2 -C 6 alkynyl means an alkynyl radical having 2 or 3 carbon atoms, and 1 carbon-carbon triple bond, or having 4 or 5 carbon atoms, and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms, and up to 3 carbon-carbon triple bonds.
  • Alkynyl groups include ethynyl, propynyl and butynyl . As described above with respect to alkyl, the straight or branched portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated. An embodiment can be a C 2 -C n alkynyl.
  • aryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 10 atoms in each ring, wherein at least one ring is aromatic.
  • aryl elements include phenyl, naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl .
  • the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.
  • the substituted aryls included in this invention include substitution at any suitable position with amines, substituted amines, alkylamines, hydroxys and alkylhydroxys , wherein the "alkyl" portion of the alkylamines and alkylhydroxys is a C 2 -C n alkyl as defined hereinabove.
  • the substituted amines may be substituted with alkyl, alkenyl, alkynl, or aryl groups as hereinabove defined.
  • alkyl, alkenyl, alkynyl, and aryl substituents may be unsubstituted or unsubstituted, unless specifically defined otherwise.
  • a (Ci-Ce) alkyl may be substituted with one or more substituents selected from OH, oxo, halogen, alkoxy, dialkylamino, or heterocyclyl , such as morpholinyl, piperidinyl, and so on.
  • alkyl, alkenyl, and alkynyl groups can be further substituted by replacing one or more hydrogen atoms by non-hydrogen groups described herein to the extent possible.
  • non-hydrogen groups include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.
  • substituted means that a given structure has a substituent which can be an alkyl, alkenyl, or aryl group as defined above.
  • the term shall be deemed to include multiple degrees of substitution by a named substitutent .
  • the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the
  • administering an agent may be performed using any of the various methods or delivery systems well known to those skilled in the art.
  • the administering can be performed, for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermalIy, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneousIy, intraadiposally, intraarticularly, intrathecally, into a cerebral ventricle, intraventicularly, intratumorally, into cerebral parenchyma or intraparenchchymally .
  • compositions in accordance with the invention may be used but are only representative of the many possible systems envisioned for administering compositions in accordance with the invention.
  • Injectable drug delivery systems include solutions, suspensions, gels, microspheres and polymeric injectables, and can comprise excipients such as solubility-altering agents (e.g., ethanol, propylene glycol and sucrose) and polymers (e.g., polycaprylactones and PLGA' s).
  • solubility-altering agents e.g., ethanol, propylene glycol and sucrose
  • polymers e.g., polycaprylactones and PLGA' s.
  • Implantable systems include rods and discs, and can contain excipients such as PLGA and polycaprylactone.
  • Oral delivery systems include tablets and capsules. These can contain excipients such as binders (e.g., hydroxypropylmethylcellulose, polyvinyl pyrilodone, other cellulosic materials and starch), diluents (e.g., lactose and other sugars, starch, dicalcium phosphate and cellulosic materials), disintegrating agents (e.g., starch polymers and cellulosic materials) and lubricating agents (e.g., stearates and talc) .
  • excipients such as binders (e.g., hydroxypropylmethylcellulose, polyvinyl pyrilodone, other cellulosic materials and starch), diluents (e.g., lactose and other sugars, starch, dicalcium phosphate and cellulosic materials), disintegrating agents (e.g., starch polymers and cellulosic materials) and lubricating agents (
  • Transmucosal delivery systems include patches, tablets, suppositories, pessaries, gels and creams, and can contain excipients such as solubilizers and enhancers (e.g., propylene glycol, bile salts and amino acids), and other vehicles (e.g., polyethylene glycol, fatty acid esters and derivatives, and hydrophilic polymers such as hydroxypropylmethylcellulose and hyaluronic acid) .
  • solubilizers and enhancers e.g., propylene glycol, bile salts and amino acids
  • other vehicles e.g., polyethylene glycol, fatty acid esters and derivatives, and hydrophilic polymers such as hydroxypropylmethylcellulose and hyaluronic acid
  • Dermal delivery systems include, for example, aqueous and nonaqueous gels, creams, multiple emulsions, microemulsions, liposomes, ointments, aqueous and nonaqueous solutions, lotions, aerosols, hydrocarbon bases and powders, and can contain excipients such as solubilizers, permeation enhancers (e.g., fatty acids, fatty acid esters, fatty alcohols and amino acids), and hydrophilic polymers (e.g., polycarbophil and polyvinylpyrolidone) .
  • the pharmaceutically acceptable carrier is a liposome or a transdermal enhancer.
  • Solutions, suspensions and powders for reconstitutable delivery systems include vehicles such as suspending agents (e.g., gums, zanthans, cellulosics and sugars), humectants (e.g., sorbitol), solubilizers (e.g., ethanol, water, PEG and propylene glycol), surfactants (e.g., sodium lauryl sulfate, Spans, Tweens, and cetyl pyridine), preservatives and antioxidants (e.g., parabens, vitamins E and C, and ascorbic acid), anti-caking agents, coating agents, and chelating agents (e.g., EDTA).
  • suspending agents e.g., gums, zanthans, cellulosics and sugars
  • humectants e.g., sorbitol
  • solubilizers e.g., ethanol, water, PEG and propylene glycol
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • the compounds described herein are useful for the prevention and/or treatment of neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, motor neuron diseases such as amyotrophic lateral sclerosis, and other neurodegenerative diseases collectively known as tauopathies.
  • the compounds increase the phosphorylation of several regulatory proteins including Akt .
  • these compounds slightly stimulate cell proliferation and increases phosphorylation of Akt in human cancer cell lines tested including SH-SY5Y.
  • Compound 100 and Compound 102 also increased Akt phosphorylation in the cell lines tested, growing as xenografts in SCID mice, as set forth in the examples herein.
  • the Compound-100 series of drugs increase cellular phosphorylated Akt at low non-toxic doses and also increase acetylation of histones in neurons of the intact animal, these compounds are useful for the treatment of neurodegenerative diseases, particularly Alzheimer's disease and all other tauopathies. While each of the compounds tested increase Akt phosphorylation of multiple tumor cell lines, they also increase Akt phosphorylation of the neuroblastoma cell line SH-SY5Y, a model of dopamine neurons.
  • Compound 100 and Compound 102 show that each of these has properties that enhance their entry into the brain.
  • these drugs are neuroprotective and useful for the prevention and/or treatment of neurodegereratve disease.
  • the mechanism by which the Compound 100 series of compounds exert their neuroprotective effect may be by increasing the intra-neuronal cell activity of Akt-1 and enhancing the phosphorylation of GSK-3B.
  • Akt-1 intra-neuronal cell activity
  • GSK-3B phosphorylation of GSK-3B
  • Each of these compounds when given by intraperitoneal injection, increase Akt phosphorylation in mouse neurons .
  • This increase in Akt phosphorylation is associated with an increase in the phosphorylation of GSK-3 ⁇ .
  • Increased phosphorylation of GSK-3 ⁇ is known to decrease its activity. Therefore, chronic suppression of GSK-3 ⁇ activity by compound 100 homologs may reduce tau phosphorylation.
  • the compound 200 series which include compounds 201, 207 (a) and 203-214, the structures of which are shown in Table 2, are HDAC inhibitors.
  • Table 1 Compouns 100-108 and 111
  • Human medulloblastoma DAOY cells were implanted subcutaneousIy in SCID mice. Mice were then treated with 0.03 mg/20 gram mouse with Compound 100 or vehicle alone. After 4 hours and 24 hours, western blots were made for phosphorylated Akt (p-Akt) , total Akt, and beta actin. Control cells at both time points had only trace amount of p-Akt and substantial amounts of total Akt and beta actin. Exposure to compound 100 revealed induction of p- Akt and an increase in total Akt relative to beta actin, as shown in Figure 3.
  • Human glioblastoma U87 cells were implanted subcutaneousIy in SCID mice. Mice were then treated with 0.03 mg/20 gram mouse with Compound 100 or vehicle alone. After 4 hours, western blots were made for p-Akt, total Akt, and beta actin. Control cells showed only trace amounts of p-Akt and substantial amounts of total Akt and beta actin. Exposure to Compound 100 revealed induction of p-Akt and an increast in total Akt relative to beta actin, as shown in in Figure 5.
  • mice Normal mice were treated with Compound 100 or Compound 102 at a dose of 0.03mg/20 gram mouse, or with vehicle. After 4 hours of exposure, treated and control animals were sacrificed and western blots for acetylated histone 3 and histone 4 were made. As showin in Figure 6, both druges increased acetylation of the histones compared to control tissue.
  • Human glioblastoma cells U87, were grown in culture and exposed to Compound 100 or vehicle alone. After 4 hours, western blots were made for p-Akt, total Akt, and beta actin. Control cells showed only trace amounts of p-Akt and substantial amounts of total Akt and beta actin. Exposure to Compound 100 revealed induction of p-Akt and an increase in total akt relative to beta actin, as shown in Figure 4.
  • HDACi class I and II HDAC inhibitor
  • P2Ai protein phosphatase 2A inihibitor
  • Neurons were chronically or acutely treated with each compound and exposed to environmental stress (replacement of the culture medium with a saline PBS based solution for one hour followed by removal of the PBS medium and restoration of standard neuronal culture medium) and then observed for survival (Fig. 6) .
  • Compound 201 displayed marked neurotrophic effects as evidenced by maintenance for up to 21 days neuronal cell numbers.
  • cells exposed to either DMSO (the vehicle used for the compounds) or just saline showed a 3.5 fold reduction in cell numbers (Fig. 7) .
  • Compound 102 had little effect on cell number.
  • AMPA/Kainate responses to exposure to glutamate as measured by calcium flux are characterized by fast desensitization (i.e. very little measurable calcium increase)
  • NMDA responses are characterized by an elevation of calcium concentration that persists as long as glutamate is applied.
  • glutamate responsiveness dependent on NMDA receptor expression A typical response of neurons in culture to glutamate characteristic of the NMDA receptors consists of a rapid increase and a high plateau phase of calcium ( Figures 8-10) . Repeat experiments showed variability in the extent of this response indicating that the time-point in culture is a moment at which NMDA receptor expression is variable.

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Abstract

L'invention porte sur des méthodes de traitement de maladies neurodégénératives comprenant l'administration au sujet d'un composé représenté par la structure : (1) dans laquelle α et R1-R8 sont tels que décrits dans la description, ou d'un composé représenté par la structure : (11) dans laquelle Y, Z et R21, R24/R25 et R31-R33 sont décrits dans la description.
EP09803262.6A 2008-08-01 2009-07-29 Agents neuroprotecteurs pour la prévention et le traitement de maladies neurodégénératives Not-in-force EP2318005B1 (fr)

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CA2730148A1 (fr) 2010-02-04
AU2009277086B2 (en) 2015-12-10
EP2318005B1 (fr) 2017-11-01
US20110287537A1 (en) 2011-11-24
WO2010014220A1 (fr) 2010-02-04
CA2730148C (fr) 2018-04-03
US20100029640A1 (en) 2010-02-04
EP2318005A4 (fr) 2012-05-16

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